Switching from Dual Antiplatelet Therapy with Aspirin Plus a P2Y₁₂ Inhibitor to Dual Pathway Inhibition with Aspirin Plus Vascular-Dose Rivaroxaban: The Switching Anti-Platelet and Anti-Coagulant Therapy (SWAP-AC) Study

Abstract

Background To date, there are no data on switching to dual pathway inhibition (DPI) patients who have completed a guideline-recommended dual antiplatelet therapy (DAPT) regimen.

Objectives To assess the feasibility of switching from DAPT to DPI and to compare the pharmacodynamic (PD) profiles of these treatments.

Methods This was a prospective, randomized, PD study conducted in 90 patients with chronic coronary syndrome (CCS) on DAPT with aspirin (81 mg/qd) plus a P2Y₁₂ inhibitor (clopidogrel [75 mg/qd; n = 30], ticagrelor [90 mg/bid; n = 30], or prasugrel [10 mg/qd; n = 30]). Patients in each cohort were randomized to maintain DAPT or switch to DPI (aspirin 81 mg/qd plus rivaroxaban 2.5 mg/bid). PD assessments included: VerifyNow P2Y₁₂ reaction units; light transmittance aggregometry following stimuli with adenosine diphosphate (ADP), tissue factor (TF), and a combination of collagen, ADP, and TF (maximum platelet aggregation %); thrombin generation (TG). Assays were performed at baseline and 30 days postrandomization.

Results Switching from DAPT to DPI occurred without major side effects. DAPT was associated with enhanced P2Y₁₂ inhibition, while DPI with reduced TG. Platelet-mediated global thrombogenicity (primary endpoint) showed no differences between DAPT and DPI in the ticagrelor (14.5% [0.0–63.0] vs. 20.0% [0.0–70.0]; p = 0.477) and prasugrel (20.0% [0.0–66.0] vs. 4.0% [0.0–70.0]; p = 0.482), but not clopidogrel (27.0% [0.0–68.0] vs. 53.0% [0.0–81.0]; p = 0.011), cohorts.

Conclusion In patients with CCS, switching from different DAPT regimens to DPI was feasible, showing enhanced P2Y₁₂ inhibition with DAPT and reduced TG with DPI, with no differences in platelet-mediated global thrombogenicity between DPI and ticagrelor- and prasugrel-, but not clopidogrel-, based DAPT.

Clinical Trial Registration http://www.clinicaltrials.gov Unique Identifier: NCT04006288.

Keywords

platelets - pharmacodynamic - dual antiplatelet therapy - aspirin - clopidogrel - ticagrelor - prasugrel - dual pathway inhibition - rivaroxaban

• References

• 1 Bhatt DL, Eagle KA, Ohman EM. et al; REACH Registry Investigators. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010; 304 (12) 1350-1357
• 2 Baigent C, Blackwell L, Collins R. et al; Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373 (9678): 1849-1860
• 3 Lawton JS, Tamis-Holland JE, Bangalore S. et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022; 145 (03) e18-e114
• 4 Collet JP, Thiele H, Barbato E. et al; ESC Scientific Document Group. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021; 42 (14) 1289-1367
• 5 Knuuti J, Wijns W, Saraste A. et al; ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020; 41 (03) 407-477
• 6 Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
• 7 Capodanno D, Bhatt DL, Eikelboom JW. et al. Dual-pathway inhibition for secondary and tertiary antithrombotic prevention in cardiovascular disease. Nat Rev Cardiol 2020; 17 (04) 242-257
• 8 Weitz JI, Angiolillo DJ, Geisler T, Heitmeier S. Dual pathway inhibition for vascular protection in patients with atherosclerotic disease: rationale and review of the evidence. Thromb Haemost 2020; 120 (08) 1147-1158
• 9 Mehran R, Rao SV, Bhatt DL. et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123 (23) 2736-2747
• 10 Urban P, Mehran R, Colleran R. et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk. Eur Heart J 2019; 40 (31) 2632-2653
• 11 Galli M, Franchi F, Rollini F. et al. Platelet P2Y12 inhibiting therapy in adjunct to vascular dose of rivaroxaban or aspirin: a pharmacodynamic study of dual pathway inhibition vs. dual antiplatelet therapy. Eur Heart J Cardiovasc Pharmacother 2022; 8 (07) 728-737
• 12 Galli M, Franchi F, Rollini F. et al. Pharmacodynamic profiles of dual-pathway inhibition with or without clopidogrel versus dual antiplatelet therapy in patients with atherosclerotic disease. Thromb Haemost 2022; 122 (08) 1341-1351
• 13 Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract 2004; 10 (02) 307-312
• 14 Rajadhyaksha V. Conducting feasibilities in clinical trials: an investment to ensure a good study. Perspect Clin Res 2010; 1 (03) 106-109
• 15 Franchi F, Rollini F, Rivas A. et al. Platelet inhibition with cangrelor and crushed ticagrelor in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Circulation 2019; 139 (14) 1661-1670
• 16 Rollini F, Franchi F, Hu J. et al. Crushed prasugrel tablets in patients with STEMI undergoing primary percutaneous coronary intervention: the CRUSH study. J Am Coll Cardiol 2016; 67 (17) 1994-2004
• 17 Bonaca MP, Bhatt DL, Cohen M. et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372 (19) 1791-1800
• 18 Mauri L, Kereiakes DJ, Yeh RW. et al; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371 (23) 2155-2166
• 19 Eikelboom JW, Bhatt DL, Fox KAA. et al. Mortality benefit of rivaroxaban plus aspirin in patients with chronic coronary or peripheral artery disease. J Am Coll Cardiol 2021; 78 (01) 14-23
• 20 Perera KS, Ng KKH, Nayar S. et al. Association between low-dose rivaroxaban with or without aspirin and ischemic stroke subtypes: a secondary analysis of the COMPASS trial. JAMA Neurol 2020; 77 (01) 43-48
• 21 Eikelboom JW, Bosch JJ, Connolly SJ. et al. Major bleeding in patients with coronary or peripheral artery disease treated with rivaroxaban plus aspirin. J Am Coll Cardiol 2019; 74 (12) 1519-1528
• 22 Siegal DM, Curnutte JT, Connolly SJ. et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373 (25) 2413-2424
• 23 Angiolillo DJ, Galli M, Collet JP, Kastrati A, O'Donoghue ML. Antiplatelet therapy after percutaneous coronary intervention. EuroIntervention 2022; 17 (17) e1371-e1396
• 24 Capodanno D, Bhatt DL, Gibson CM. et al. Bleeding avoidance strategies in percutaneous coronary intervention. Nat Rev Cardiol 2022; 19 (02) 117-132
• 25 Palmerini T, Benedetto U, Bacchi-Reggiani L. et al. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials. Lancet 2015; 385 (9985): 2371-2382
• 26 Storey RF, Sanderson HM, White AE, May JA, Cameron KE, Heptinstall S. The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol 2000; 110 (04) 925-934
• 27 Angiolillo DJ, Ueno M, Goto S. Basic principles of platelet biology and clinical implications. Circ J 2010; 74 (04) 597-607
• 28 Becker EM, Perzborn E, Klipp A. et al. Effects of rivaroxaban, acetylsalicylic acid and clopidogrel as monotherapy and in combination in a porcine model of stent thrombosis. J Thromb Haemost 2012; 10 (12) 2470-2480
• 29 Perzborn E, Heitmeier S, Laux V. Effects of rivaroxaban on platelet activation and platelet-coagulation pathway interaction: in vitro and in vivo studies. J Cardiovasc Pharmacol Ther 2015; 20 (06) 554-562
• 30 Ohman EM, Roe MT, Steg PG. et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet 2017; 389 (10081): 1799-1808
• 31 EMA. Guideline on adjustment for baseline covariates in clinical trials. 2015. Accessed June 7, 2023 at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-adjustment-baseline-covariates-clinical-trials_en.pdf